PROJECT SUMMARY Lung adenocarcinomas (LUADs) frequently harbor mutations in genes encoding components of the Epidermal Growth Factor Receptor (EGFR) signaling pathway. Mutations are found in EGFR itself, related receptor tyrosine kinases (RTKs) and in downstream signaling molecules. Emerging evidence from sequencing studies of LUADs by our group and others has also revealed mutations in genes encoding negative regulators of RTKs including the CBL proto-oncogene, an E3 ubiquitin ligase that targets EGFR for degradation. Despite the convergence of these genetic alterations on related and overlapping signaling pathways, each specific mutation determines the sensitivity of the disease to different therapies and defines unique clinical subsets of lung cancer each with its own set of characteristics. For example, mutations in EGFR are the only genetic alteration associated with sensitivity to the tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. Tumors with these mutations represent a paradigm for the use of targeted therapies in lung cancer. However, responses to EGFR TKIs are not sustained and tumors become resistant on average within a year after drug-treatment is initiated. Acquired resistance to therapies targeting the EGFR is a major impediment to cures or durable responses for these patients. For other subsets of tumors, such as those harboring mutations in CBL, very little is known to date on the biology and drug sensitivity of these tumors. In this project, centered on the EGFR pathway in LUADs, we seek 1) to clarify the mechanisms of acquired resistance to EGFR-directed therapies in EGFR mutant LUADs, 2) to develop rational approaches to overcome resistance to EGFR-directed therapies and, 3) to understand the vulnerabilities of LUADs with mutations in other genes that control EGFR signaling.